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Compounds for imaging and therapy
8299285 Compounds for imaging and therapy
Patent Drawings:Drawing: 8299285-3    Drawing: 8299285-4    Drawing: 8299285-5    Drawing: 8299285-6    Drawing: 8299285-7    
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Inventor: Dilworth, et al.
Date Issued: October 30, 2012
Application: 11/988,230
Filed: July 5, 2006
Inventors: Dilworth; Jonathan Robin (Oxford, GB)
Peach; Josephine Mary (Oxford, GB)
Heslop; Julia May (Oxford, GB)
Donnelly; Paul Stephen (Melbourne, AU)
Assignee: Isis Innovation Limited (Summertown, Oxford, GB)
Primary Examiner: Gonzalez; Porfirio Nazario
Assistant Examiner:
Attorney Or Agent: Nixon & Vanderhye P.C.
U.S. Class: 556/34; 424/9.36; 424/9.361; 546/12; 548/106; 549/210; 556/35; 558/35; 564/243
Field Of Search: 558/35; 556/34; 556/35; 549/210; 548/106; 546/12; 564/243; 514/494; 514/499; 514/501; 424/9.36; 424/9.361
International Class: C07F 1/08; A61B 5/055; A61K 31/00
U.S Patent Documents:
Foreign Patent Documents: 0 306 168; 0 606 683; 0 726 077; 1528968; 793802; 1143940; 1 448 295; 7-72571; 92/07860
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Abstract: A metal complex of formula (III) wherein: M is a transition metal and A1, A2, X, X', Y, L1', R1' and R2' are as defined herein, is useful in medical imaging and therapy.
Claim: The invention claimed is:

1. A metal complex of formula (III): ##STR00109## wherein: M is a Cu; A1 is: ##STR00110## n is 0 or an integer of 1 to 5; A2, X and Y are as defined in (i), (ii) and(iii) which follow: (i) A2 is ##STR00111## X is N or P and A1 is attached to X via a double bond, or X is O, S, N(R5) or P(R5) and A1 is attached to X via a single bond; and Y is N, O, P, S, N(R5), O(R5), P(R5) or S(R5); or (ii) X is N or P and A1 isattached to X via a double bond, or X is O, S, N(R5) or P(R5) and A1 is attached to X via a single bond; and Y and A2 together represent a moiety of formula (B): ##STR00112## wherein the ring that is substituted by L1-R1 is a 5- to 11-memberedheterocyclic group; or (iii) X, A2 and Y together represent ##STR00113## wherein T is OH, O--, COOH or C(O)O-- and rings b and c are aromatic C.sub.6-10 carbocyclic or 5 to 11 membered aromatic heterocyclic groups; X' is N and A1 is attached to X' viaa double bond, or X' is N(R5), O, S or P(R5) and A1 is attached to X' via a single bond; L1 and L1', which are the same or different, are each independently selected from a covalent bond and a linker group selected from --C(O)--, -alk--C(O)--,--C(O)O--, -alk--C(O)O--, --OC(O)--, -alk--OC(O)--, --O--, -alk--O--, --N(R7)--, -alk--N(R7)--, --N(R7)C(O), -alk--N(R7)C(O)--, --C(O)N(R7), -alk--C(O)N(R7), --C(S)--, -alk--C(S)--, --S--, -alk--S--, --C(S)N(R7)--, -alk--C(S)N(R7)--, --N(R7)C(S)--,-alk--N(R7)C(S)--, --S(O).sub.2N(R7)--, -alk--S(O).sub.2N(R7)--, --N(R7)S(O).sub.2--, -alk--N(R7)S(O).sub.2--, --S(O)--, -alk--S(O)--, --N(R7)C(O)O--, -alk--N(R7)C(O)O--, --OC(O)N(R7)--, -alk--OC(O)N(R7)--, --N(R7)C(O)N(R7)--, -alk--N(R7)C(O)N(R7)--,--N(R7)C(S)N(R7)--, -alk--N(R7)C(S)N(R7)--, --N.dbd.C(R7)--, -alk--N.dbd.C(R7)--, --C(R7)=N-- and -alk--C(R7)=N--; R1 and R1', which are the same or different, are each independently selected from hydrogen, Z, L3--Z, L3-alk--Z, --V--L3--Z,--V--L3-alk--Z, alk--V--L3--Z, -alk--V--L3-alk--Z and a substituted or unsubstituted group selected from an alkyl, amino, carbocyclic, cycloalkyl, heterocyclic, -alk-carbocyclic, -alk-cycloalkyl and -alk-heterocyclic group, which group may be furthersubstituted by L3--Z or L3-alk--Z, wherein L3 is as defined above for L1 and L1', --V-- is a linking group of the following formula: ##STR00114## wherein P2 and Q2 are independently selected from N, O, P and S and M2 is a metal atom, and Z is a moietyselected from a biologically active molecule, a fluorophore, a cytotoxin, an amino acid, a peptide, an oligopeptide, a polypeptide, a sugar, a group containing a label, a leaving group which is replaceable by a group containing a label, and a complex ofCu, Zn or Ni with a bis(thiosemicarbazone) or a thiosemicarbazone; -alk- is an alkylene, alkenylene or alkynylene group based on an alkyl, alkenyl or alkynyl group; R2 and R2', which are the same or different, are each independently selected from H,C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.6 alkoxy; each R3 is independently selected from H, C.sub.1-C.sub.6 alkyl, heterocyclic group and phenyl; each R4 is independently selected from H, C.sub.1-C.sub.6 alkyl, heterocyclic group and phenyl; each R5is independently selected from H, C.sub.1-C.sub.6 alkyl and a group comprising an electron donor group, which donor group is separated by two carbon atoms from the O, N, S or P atom to which R5 is attached; R7 is H, alkyl or cycloalkyl; each R10 isindependently selected from H, C.sub.1-C.sub.6 alkyl, heterocyclic group and phenyl; and L2 is --C(O)-- or a covalent bond; with the proviso that when X and X' are both N, Y is S, A1 is (a') and A2 is (d) then either the moiety represented by L1-R1 orthe moiety represented by L1'-R1' is other than H, unsubstituted alkyl or unsubstituted alkoxy.

2. A metal complex according to claim 1 with the proviso that when X and X' both N, Y is S, A1 is (a') and A2 is (d) then either R1 or is Z, L3--Z, L3-alk--Z, --V--L3--Z, --V--L3-alk--Z, -alk--V--L3--Z, -alk--V--L3-alk--Z or a group selectedfrom an alkyl, amino, carbocyclic, cycloalkyl, heterocyclic, -alk-carbocyclic--, alk-cycloalkyl and -alk-heterocyclic group, which group is further substituted by L3--Z or L3-alk--Z.

3. A metal complex according to claim 1 wherein either: A2, X and Y are as defined in (ii) or (iii); A2, X and Y are as defined in (i) wherein A2 is (e); or either R1 or R1' is Z, L3--Z, L3-alk--Z, --V--L3--Z, --V--L3-alk--Z, -alk--V--L3--Z,-alk--V--L3-alk--Z or a group selected from an alkyl, amino, carbocyclic, cycloalkyl, heterocyclic, -alk-carbocyclic, -alk-cycloalkyl and -alk-heterocyclic group, which group is further substituted by L3--Z or L3-alk--Z.

4. A metal complex according to claim 1 wherein A1 is (a'), (b'), (d') or (e') and n is 2.

5. A metal complex according to claim 1 wherein A1 is (d').

6. A metal complex according to claim 1 wherein n=0.

7. A complex according to claim 1, wherein: M is Cu; L1' is a covalent bond; R1' is H or a group selected from alkyl, alkoxy and phenyl; and A2 is of the formula (d) as defined in claim 1, or A2 and Y together represent a group of theformula (B) as defined in claim 1 and wherein, in formulae (d) and (B), L1 is as defined in claim 1 and R1 is Z, L3--Z, L3-alk--Z or a group substituted by L3--Z or L3-alk--Z, wherein said group, L3 and Z are as defined in claim 1.

8. A complex according to claim 1 wherein: M is Cu; X is N; A1 is a group of formula (a') as defined in claim 1; A2 and Y together represent a group of formula (C): ##STR00115## in which L1 and R1 are as defined in claim 1; L1' is acovalent bond; R1' is H or a group selected from alkyl, alkoxy and phenyl; and R2' is as defined in claim 1.

9. A metal complex according to claim 1 which is of formula (IIa): ##STR00116## wherein: M is Cu; A1 is: ##STR00117## X is N and A1 is attached to X via a double bond, or X is N(R11) and A1 is attached to X via a single bond; X' is N and A1is attached to X' via a double bond, or X' is N(R11) and A1 is attached to X' via a single bond; n is O or an integer of 1 to 5; each R11 is independently selected from H and C.sub.1-C.sub.6 alkyl; each R10 is independently selected from H,C.sub.1-C.sub.6 alkyl and phenyl; R and R', which are the same or different, are each H or a group selected from C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy and phenyl; R2 is H or a group selected from C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.6alkoxy; each R3, which are the same or different, is H or a group selected from C.sub.1-C.sub.6 alkyl and phenyl; L1 is a covalent bond or a linker group selected from --C(O)--, -alk--C(O)--, --C(O)O--, -alk--C(O)O--, --OC(O)--, -alk--OC(O)--, --O--,-alk--O--, --N(R7)--, -alk--N(R7)--, --N(R7)C(O), -alk--N(R7)C(O)--, --C(O)N(R7), -alk--C(O)N(R7), --C(S)--, -alk--C(S)--, --S--, -alk--S--, --C(S)N(R7)--, -alk--C(S)N(R7)--, --N(R7)C(S)--, -alk--N(R7)C(S)--, --S(O).sub.2N(R7)--, -alk--S(O).sub.2N(R7)--,--N(R7)S(O).sub.2--, -alk--N(R7)S(O).sub.2--, --S(O)--, -alk--S(O)--, --N(R7)C(O)O--, -alk--N(R7)C(O)O--, --OC(O)N(R7)--, -alk--OC(O)N(R7)--, --N(R7)C(O)N(R7)--, -alk--N(R7)C(O)N(R7)--, --N(R7)C(S)N(R7)--, -alk--N(R7)C(S)N(R7)--, --N.dbd.C(R7)--,-alk--N.dbd.C(R7)--, --C(R7)=N-- and -alk--C(R7)=N--; R7 is H, alkyl or cycloalkyl; and R1 is Z, L3--Z, -alk--L3--Z or a group selected from an alkyl, carbocyclic, cycloalkyl, heterocyclic, -alk-carbocyclic, -alk-cycloalkyl and -alk-heterocyclic group,which group is further substituted by L3--Z or L3-alk--Z, wherein L3 is as defined above for L1 and Z is a moiety selected from a biologically active molecule, a fluorophore, a cytotoxin, an amino acid, a peptide, an oligopeptide, a polypeptide, a groupcontaining a label, a leaving group which is replaceable by a group containing a label, and a Cu or Zn complex of a bis(thiosemicarbazone) or of a thiosemicarbazone.

10. A metal complex according to claim 1 which is of formula (IIIb): ##STR00118## wherein M is Cu; R and R', which are the same or different, are each H or a group selected from C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy and phenyl; A1' isa group of formula (a'), (b'), (c'), (d'), (e'), (f'), (g'), (h') or (i'): ##STR00119## wherein each R3, which are the same or different, is H or a group selected from C.sub.1-C.sub.6 alkyl and phenyl; each L2 is independently selected from --C(O)-- anda covalent bond; each R10 is independently selected from H, C.sub.1-C.sub.6 alkyl and phenyl; and n is 0 or an integer of 1 to 5; each R4, which are the same or different, is independently selected from H, C.sub.1-C.sub.6 alkyl and phenyl; X is N orP and A1' is attached to X via a double bond, or X is selected from O, S, N(R5) and P(R5) and A1' is attached to X via a single bond; Y is selected from O, S, N(R5), P(R5), O(R5) and S(R5); each R5 is independently selected from H, C.sub.1-C.sub.6alkyl and a group comprising an electron donor group, which donor group is separated by two carbon atoms from the O, N, S or P atom to which R5 is attached.

11. A complex according to claim 1 wherein the Cu is .sup.60Cu, .sup.61Cu, .sup.62Cu, 64Cu or .sup.67Cu.

12. A complex according to claim 1 which is hypoxic selective.

13. A complex according to claim 1 wherein Z is a Cu complex of a bis(thiosemicarbazone) or of a thiosemicarbazone, thereby creating a dimer wherein two bis(thiosemicarbazone) or thiosemicarbazone Cu complexes are linked by -L1-R1-L1--,L1-alk--R1-L1--, -L1-R1-alk--L1- or -L1-alk--R1-alk--L1- wherein L1 and R1 are as defined in claim 1.

14. A pharmaceutical composition comprising a complex as defined in claim 1 and a pharmaceutically acceptable carrier.

15. A composition according to claim 14 wherein the complex is hypoxic selective.

16. A diagnostic agent or medical imaging agent which comprises a complex as defined in claim 1 which is hypoxic selective.

17. A composition according to claim 15 wherein hypoxic selectivity arises from the redox behaviour of the metal at the centre of the complex.

18. An agent according to claim 16 wherein the complex comprises a fluorophore and wherein the agent is suitable for optical and positron emission tomography (PET) imaging and/or for non-radioactive optical imaging.

19. An agent according to claim 16 wherein the complex comprises a radionuclide and the agent is suitable for the imaging of hypoxic tumours.

20. A diagnostic agent or a medical imaging agent which comprises a complex as defined in claim 1 which is not hypoxic selective and in which Z is a biologically active molecule which serves to target the complex to the desired site in vivo.

21. An agent according to claim 20 in which the biologically active molecule is a monoclonal antibody, a peptide, an oligopeptide or a polypeptide.

22. A method of imaging a cell or in vitro biopsy sample, which method comprises: (a) contacting the cell or in vitro biopsy sample with a complex as defined in claim 1; and (b) imaging the cell or in vitro biopsy sample.

23. A method of imaging a patient in need thereof, which method comprises: (a) administering to the patient a complex as defined in claim 1; and (b) imaging the patient.
Description:
 
 
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